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Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1α expression, resulting in reduced angiogenesis

Abstract

Until recently, the use of Se-methylselenocysteine (MSC) as selective modulator of the antitumor activity and selectivity of anticancer drugs including irinotecan, a topoisomerase I poison, had not been evaluated. Therapeutic synergy between MSC and irinotecan was demonstrated by our laboratory in mice bearing human squamous cell carcinoma of the head and neck tumors. In FaDu xenografts, a poorly differentiated tumor-expressing mutant p53, the cure rate was increased from 30% with irinotecan alone to 100% with the combination of irinotecan and MSC. Cellular exposure to cytotoxic concentration of SN-38, the active metabolite of irinotecan (0.1 μ M) alone and in combination with noncytotoxic concentration of MSC (10 μ M) did not result in additional enhancement of chk2 phosphorylation and downregulation of specific DNA replication-associated proteins, cdc6, MCM2, cdc25A, nor increase in PARP cleavage, caspase activation and the 30–300 kb DNA fragmentation induced by SN-38 treatment. MSC did not alter significantly markers associated with apoptosis, nor potentiate irinotecan-induced apoptosis. These results indicate that apoptosis is unlikely to be one of the main mechanism associated with the observed in vivo therapeutic synergy. In contrast, significant downregulation of cyclooxygenase-2 (COX-2) expression and activity was observed in the cells exposed to SN-38 in combination with MSC compared to SN-38 alone. Moreover, the inhibition of PGE2 production was also observed in the cells treated with the combination as compared with SN-38 alone. Analysis of tumor tissues at 24 h after treatment with synergistic modality of irinotecan and MSC revealed significant downregulation of COX-2, inducible nitric oxide synthase (iNOS) and hypoxia-induced factor-1α expression (HIF 1α). Moreover, decreased microvessel density was observed after irinotecan treatment with the addition of MSC. These results suggest that observed therapeutic synergy correlates with the inhibition of neoangiogenesis through the downregulation of COX-2, iNOS and HIF-1α expression.

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References

  • Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS . (2005). Life Sci 76: 2315–2328.

  • Apostolou S, Klein JO, Mitsuuchi Y, Shetler JN, Poulikakos PI, Jhanwar SC et al. (2004). Oncogene 23: 5032–5040.

  • Azrak RG, Cao S, Slocum HK, Toth K, Durrani FA, Yin MB et al. (2004). Clin Cancer Res 10: 1121–1129.

  • Bhattacharya A, Toth K, Mazurchuk R, Spernyak JA, Slocum HK, Pendyala L et al. (2004). Clin Cancer Res 10: 8005–8017.

  • Bing RJ, Miyataka M, Rich KA, Hanson N, Wang X, Slosser HD et al. (2001). Clin Cancer Res 7: 3385–3392.

  • Bussolati B, Deambrosis I, Russo S, Deregibus MC, Camussi G . (2003). FASEB J 17: 1159–1161.

  • Cao S, Durrani FA, Rustum YM . (2004). Clin Cancer Res 10: 2561–2569.

  • Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC et al. (2004). Proc Natl Acad Sci USA 101: 591–596.

  • Chapple KS, Scott N, Guillou PJ, Coletta PL, Hull MA . (2002). J Pathol 198: 435–441.

  • Chen Y, Yang L, Lee TJ . (2000). Biochem Pharmacol 59: 1445–1457.

  • Cherukuri DP, Goulet AC, Inoue H, Nelson MA . (2005). Cancer Biol Ther 4: 175–180.

  • Chun KS, Cha HH, Shin JW, Na HK, Park KK, Chung WY et al. (2004). Carcinogenesis 25: 445–454.

  • Cianchi F, Cortesini C, Bechi P, Fantappie O, Messerini L, Vannacci A et al. (2001). Gastroenterology 121: 1339–1347.

  • Cianchi F, Cortesini C, Fantappie O, Messerini L, Sardi I, Lasagna N et al. (2004). Clin Cancer Res 10: 2694–2704.

  • Cianchi F, Cortesini C, Fantappie O, Messerini L, Schiavone N, Vannacci A et al. (2003). Am J Pathol 162: 793–801.

  • Collins JA, Schandi CA, Young KK, Vesely J, Willingham MC . (1997). J Histochem Cytochem 45: 923–934.

  • Deregibus MC, Buttiglieri S, Russo S, Bussolati B, Camussi G . (2003). J Biol Chem 278: 18008–18014.

  • Dimmeler S, Zeiher AM . (2000). Circ Res 86: 4–5.

  • Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N et al. (1998). Cell 94: 715–725.

  • Gallo O, Fabbroni V, Sardi I, Magnelli L, Boddi V, Franchi A . (2002). Biochem Biophys Res Commun 299: 517–524.

  • Gallo O, Masini E, Morbidelli L, Franchi A, Fini-Storchi I, Vergari WA et al. (1998). J Nat Cancer Inst 90: 587–595.

  • Ganther HE . (1999). Carcinogenesis 20: 1657–1666.

  • Giaccia AJ, Shieh J, Cholon A, Brown JM . (1991). Mutat Res 263: 69–75.

  • Guo B, Cao S, Toth K, Azrak RG, Rustum YM . (2000). Clin Cancer Res 6: 718–724.

  • Hussain SP, Trivers GE, Hofseth LJ, He P, Shaikh I, Mechanic LE et al. (2004). Cancer Res 64: 6849–6853.

  • Iniguez MA, Rodriguez A, Volpert OV, Fresno M, Redondo JM . (2003). Trends Mol Med 9: 73–78.

  • Ip C, Zhu Z, Thompson HJ, Lisk D, Ganther HE . (1999). Anticancer Res 19: 2875–2880.

  • Jiang B, Xu S, Hou X, Pimentel DR, Brecher P, Cohen RA . (2004). J Biol Chem 279: 1323–1329.

  • Jiang C, Jiang W, Ip C, Ganther H, Lu J . (1999). Mol Carcinog 26: 213–225.

  • Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ et al. (1999). Nat Med 5: 1418–1423.

  • Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L . (2003). FASEB J 17: 2115–2117.

  • Kisley LR, Barrett BS, Bauer AK, Dwyer-Nield LD, Barthel B, Meyer AM et al. (2002). Cancer Res 62: 6850–6856.

  • Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML . (2002). Science 295: 858–861.

  • Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E et al. (2001). J Biol Chem 276: 18563–18569.

  • Lu J . (2001). Adv Exp Med Biol 492: 131–145.

  • Lu J, Jiang C . (2001). Nutr Cancer 40: 64–73.

  • Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM et al. (2000). Cancer Res 60: 1306–1311.

  • Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ et al. (1997). Proc Natl Acad Sci USA 94: 8104–8109.

  • Medina D, Morrison DG . (1988). Pathol Immunopathol Res 7: 187–199.

  • Merchan JR, Jayaram DR, Supko JG, He X, Bubley GJ, Sukhatme VP . (2005). Int J Cancer 113: 490–498.

  • Muller-Decker K, Neufang G, Berger I, Neumann M, Marks F, Furstenberger G . (2002). Proc Natl Acad Sci USA 99: 12483–12488.

  • Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T et al. (2003). J Biol Chem 278: 37937–37947.

  • Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE et al. (1993). EMBO J 12: 3679–3684.

  • Park SW, Lee SG, Song SH, Heo DS, Park BJ, Lee DW et al. (2003). Int J Cancer 107: 729–738.

  • Pichiule P, Chavez JC, LaManna JC . (2004). J Biol Chem 279: 12171–12180.

  • Rajnakova A, Moochhala S, Goh PM, Ngoi S . (2001). Cancer Lett 172: 177–185.

  • Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA et al. (2004). Cancer Res 64: 6845–6848.

  • Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW, Clark LC, Marshall JR . (2002). Cancer Epidemiol Biomarkers Prev 11: 1285–1291.

  • Schwartz DC, Cantor CR . (1984). Cell 37: 67–75.

  • Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK et al. (2001). Mutation Res 480/481: 243–268.

  • Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN . (1998). Cell 93: 705–716.

  • Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K . (2004). Cancer Res 64: 2030–2038.

  • Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB . (1998). Carcinogenesis 19: 711–721.

  • Yin MB, Li ZR, Cao S, Durrani FA, Azrak RG, Frank C et al. (2004). Mol Pharmacol 66: 153–160.

  • Zhou N, Xiao H, Li TK, Nur-E-Kamal A, Liu LF . (2003). J Biol Chem 278: 29532–29537.

  • Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ et al. (1997). J Clin Invest 99: 2625–2634.

  • Ziche M, Morbidelli L, Masini E, Granger H, Geppetti P, Ledda F . (1993). Biochem Biophys Res Commun 192: 1198–1203.

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Acknowledgements

We thank Linda Onetto for her secretarial assistance and Pharmacia Corporation for providing us with irinotecan and SN-38. We also acknowledge Mary M Vaughan for excellent assistance with the immunohistochemical methods. This research was supported in part by Project Grant CA65761 and a Comprehensive Cancer Center Support Grant CA16056 from the National Cancer Institute, Bethesda, MD, USA.

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Correspondence to Y M Rustum.

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Yin, MB., Li, ZR., Tóth, K. et al. Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1α expression, resulting in reduced angiogenesis. Oncogene 25, 2509–2519 (2006). https://doi.org/10.1038/sj.onc.1209073

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